1. Field of the Invention
The present invention is directed to a novel process, which utilizes novel intermediates described herein, for synthesizing carbapenem compounds.
2. Description of the Prior Art
Total syntheses of carbapenems having the generic formula ##STR2## wherein R.sup.1 is hydrogen or a conventional hydroxy-protecting group, and
R.sup.2, R.sup.3, and R.sup.4 are independently selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms;
often start with an optically active azetidinone intermediate such as that of Formula II ##STR3## where R.sup.1 is hydrogen or a conventional hydroxy-protecting group and wherein the absolute configuration at carbons 1', 3 and 4 is R, R, and R. Intermediates of Formula II, which are known per se, are key intermediates in the synthesis of carbapenem and penem antibiotics having an (R)-hydroxyethyl substituent at the 6-position of the carbapenem or penem nucleus and the absolute configuration R and S at the 5 and 6-positions, respectively. A wide variety of such compounds, including the natural fermentation product thienamycin, have been reported in the patent and scientific literature as having exceptional antibacterial activity.
Several total synthesis procedures have been reported for preparation of the above-described penem and carbapenem antibiotics, but to date such procedures have been unsatisfactory from a commercial standpoint due to the large number of steps required and the necessity of separating diastereisomer mixtures formed in such procedures.
As previously mentioned, these total synthesis procedures often start with compounds such as Formula II. Then, through a series of reactions directed at the 4-position substituent, an intermediate is synthesized which can, by conventional methods, be cyclized by reaction with the 1-position nitrogen. A synthesis of this type is illustrated in columns 4 and 5 of U.S. Pat. No. 4,383,946 to Christensen et al, and columns 2 and 3 of U.S. Pat. No. 4,318,912 to Christensen et al.
Other approaches to total synthesis, such as that shown in column 2 of U.S. Pat. No. 4,208,422 to Christensen et al, and columns 11 and 12 of U.S. Pat. No. 4,234,596 to Christensen et al, involve cyclizing intermediates substituted on both the 4-position carbon and 1-position nitrogen.
The novel process of this invention, however, proceeds through novel N-substituted azetidinone intermediates and then cyclizes to the 4-position of the azetidinone, thereby forming a carbapenem.